「突破性」：首個針對「超級淋病」的治療方法通過試驗

如果使用得當，抗生素可以扭轉抗藥性形式感染之局勢。

埃文.卡拉威 / 2023 年 11 月 1 日 / 新聞 / Nature

淋病奈瑟氏菌引起的淋病通常是無症狀的。圖片來源：Kwangshin Kim/Science Photo Library

醫護人員很快就能找到一種工具來阻止抗藥性「超級淋病」的增加。 開發該藥物的非營利組織今天宣布，數十年來第一種治療淋病的新型抗生素在大規模臨床試驗中取得了良好的結果。

每年，全世界有近 1 億人感染淋病奈瑟菌引起的淋病。 在過去的十年中，幾乎所有可用藥物都無法治癒的「超級淋病」之病例數量不斷增加，令人擔憂。 這種感染通常是無症狀的，如果不及時治療，淋病奈瑟菌會導致不孕和子宮外孕，並可能導致愛滋病毒傳播增加。

製藥公司研發的新抗生素數量很少且相差甚遠。 這種潛在的新型淋病治療藥物名為佐利氟達星 (zoliflodacin)，最初由製藥公司阿斯特捷利康 (AstraZeneca) 開發，後來由其位於麻薩諸塞州沃爾瑟姆的子公司 Entasis Therapeutics 開發。 該藥物針對一種重要的細菌酶，該酶在細胞複製過程中解開 DNA。

美國國家衛生研究院資助了一項針對179 名淋病患者的II 期臨床試驗，該試驗於2018 年報告了積極結果。但該藥物的開發一直處於「懸而未決」的狀態，直到瑞士日內瓦的一個非獲利組織全球抗生素研究與開發夥伴關係( the Global Antibiotic Research and Development Partnership , GARDP) 的成立， GARDP的執行董事 Manica Balasegaram 表示，該夥伴關係是與Entasis 合作，透過領導大規模試驗來推動這項計畫的發展。

一對一測試

該試驗招募了來自南非、泰國、美國、比利時和荷蘭的 930 名淋病患者。 參與者接受唑利氟達星（以藥丸形式給藥）或該疾病的標準治療，即注射一種名為頭孢曲松 (ceftriaxone)的抗生素，並結合口服抗生素阿奇黴素 (azithromycin)。

GARDP 在 11 月 1 日的新聞稿中報道，這些病例都不是由對頭孢曲松或阿奇黴素抗藥性的細菌引起的，但試驗發現佐利氟達星在治療感染方面與標準藥物一樣有效。 Balasegaram 補充道，該試驗還發現該藥物是安全的，並且參與者對其耐受性良好。

瑞典厄勒布魯大學醫院的微生物學家 Magnus Unemo 表示，這些結果以及新的淋病治療方法的前景「無疑具有開創性」，但他們來得不夠快。 淋病奈瑟菌的頭孢曲松抗藥性菌株已在世界各地獨立出現，目前在一些國家廣泛傳播； 烏內莫 (Unemo) 補充說，有些人也對阿奇黴素產生了抗藥性。「這種情況的發展令人嚴重擔憂，因為淋病可能無法治愈」。

但這些菌株仍然對唑利氟達星敏感。 Unemo 的團隊和其他人發現，淋病奈瑟菌可以在實驗室中進化出對唑利氟達星的抗藥性，但尚未在患者樣本中檢測到抗藥性菌株。

情況可能並非總是如此，特別是如果佐利氟達星被過度使用或誤用——例如未能足夠長的使用時間來消滅一個人體內的細菌。 「淋病已經成功地對所有類別的藥物產生了抗藥性」，Balasegaram說道。

治療和測試

為了防止對唑利氟達星產生抗藥性，該藥物僅用於治療淋病和其他性傳播感染 (STI)。 然而，何時以及如何使用該藥物將由監管機構和公共衛生機構決定。

日內瓦世界衛生組織的性傳播感染專家 Teodora Wi 表示，新的診斷方法也很重要。 在不久的將來，能夠快速區分淋病和其他性傳播感染的檢測應該會得到更廣泛的應用，但那些能夠識別抗藥性的檢測還遙遙無期。 Wi 補充道，針對抗生素抗藥性淋病的國家監測計畫也可以指導佐利氟達星的負責任使用。

「我們仍然需要解決這個問題」，Balasegaram說。 「我們不能剝奪世界各地需要這種治療的人」。

GARDP 擁有在世界大部分地區銷售該藥物的許可，Entasis 擁有其餘地區的營銷權。Balasegaram拒絕透露費用是多少。 GARDP 已經與印度製藥商達成了生產協議，Balasegaram 希望大規模生產最終意味著佐利氟達星的成本與現有治療方法大致相同——每個療程只需幾美元。

doi：https://doi.org/10.1038/d41586-023-03448-x

參考文獻：

1. Taylor, S. N.等人。《新英格蘭醫學》。379, 1835–1845 (2018)。

2. Jacobsson, S. 等。《藥理學前沿》。13、874176 (2022)。

‘Groundbreaking’: first treatment targeting ‘super-gonorrhoea’ passes trial

Antibiotic could turn the tide on drug-resistant form of the infection — if it’s used wisely.

Ewen Callaway / 01 November 2023 NEWS / Nature

The bacterium Neisseria gonorrhoeae causes gonorrhoea, which is often symptomless.

Credit: Kwangshin Kim/Science Photo Library

Medics could soon have a tool to stem the rise of drug-resistant ‘super-gonorrhoea’. The first new antibiotic in decades for treating gonorrhoea has produced good results in a large-scale clinical trial, the non-profit organization developing the drug announced today.

Each year, nearly 100 million people worldwide contract gonorrhoea, which is caused by the bacterium Neisseria gonorrhoeae. In the past decade, there has been a worrying rise in cases of ‘super-gonorrhoea’ impervious to nearly all available drugs. The infection is often symptomless and, if left untreated, N. gonorrhoeae can cause infertility and ectopic pregnancy, and can lead to increased HIV transmission.

New antibiotics are few and far between in drug-company pipelines. The potential new gonorrhoea treatment, called zoliflodacin, was developed initially by drug firm AstraZeneca and later by its spin-off Entasis Therapeutics in Waltham, Massachusetts. The drug targets an essential bacterial enzyme that untangles DNA during cell replication.

The US National Institutes of Health helped to fund a phase II clinical trial in 179 people with gonorrhoea, which reported positive result1 in 2018. But the drug’s development was “in limbo” until the Global Antibiotic Research and Development Partnership (GARDP), a non-profit organization in Geneva, Switzerland, teamed up with Entasis to push it forward by leading a large-scale trial, says Manica Balasegaram, GARDP’s executive director.

Head to head test

The trial enrolled 930 people with gonorrhoea in South Africa, Thailand, the United States, Belgium and the Netherlands. Participants received either zoliflodacin — given as a pill — or the disease’s standard treatment, an injection of an antibiotic called ceftriaxone, in combination with an oral dose of the antibiotic azithromycin.

None of the cases was caused by bacteria resistant to ceftriaxone or azithromycin, but the trial found that zoliflodacin was just as effective at curing infections as the standard drugs, GARDP reported in a 1 November press release. The trial also found that drug was safe and participants tolerated it well, Balasegaram adds.

The results — and the prospect of a new gonorrhoea treatment — are “certainly groundbreaking”, says Magnus Unemo, a microbiologist at Örebro University Hospital in Sweden. They couldn’t come soon enough. Ceftriaxone-resistant strains of N. gonorrhoeae have emerged independently around the world and are now spreading widely in some countries; some have also picked up resistance to azithromycin, Unemo adds. “This developing situation is a grave concern, because gonorrhoea might become untreatable.”

But the strains remain sensitive to zoliflodacin. Unemo’s team and others have found that N. gonorrhoeae can evolve resistance to zoliflodacin in the laboratory2, but no resistant strains have yet been detected in samples from patients.

This might not always be the case, particularly if zoliflodacin is overused or misused — for instance by failing to administer it for long enough to wipe out a person’s population of the bacteria. “Gonorrhoea has managed to develop resistance to all classes of drugs that have been thrown at it,” says Balasegaram.

Treatment and tests

To forestall resistance to zoliflodacin, the drug is being developed only as a treatment for gonorrhoea and other sexually transmitted infections (STIs). However, it will be up to regulatory and public-health agencies to decide when and how the drug can be used.

New diagnostics will also be important, says Teodora Wi, an STI specialist at the World Health Organization in Geneva. Tests that can rapidly distinguish gonorrhoea from other STIs should be more widely available in the near future, but those able to identify drug resistance are further off. National surveillance programmes for antibiotic-resistant gonorrhoea could also guide the responsible use of zoliflodacin, Wi adds.

“We still have to work this out,” says Balasegaram. “We cannot deprive people who need this treatment around the world.”

GARDP has a licence to sell the drug in most of the world and Entasis has marketing rights for the remaining territories. Balasegaram declined to say how much it would cost. GARDP already has a manufacturing deal with an Indian drugmaker, and Balasegaram hopes that large-scale production will eventually mean that zoliflodacin costs about the same as existing treatments — just a few dollars per course.

doi: https://doi.org/10.1038/d41586-023-03448-x

References

1. Taylor, S. N. et al. N. Engl. J. Med. 379, 1835–1845 (2018).
2. Jacobsson, S. et al. Front. Pharmacol. 13, 874176 (2022).